Author: Lynda Williams
medwireNews: Alterations to ABCB11 play a “pivotal role” in the development of drug-induced liver injury (DILI) from anabolic steroids (AS), US researchers reported at the 2024 AASLD The Liver Meeting in San Diego, California, USA.

“In complex diseases, the genes harbouring pathogenic variants generally have a limited effect as typically carried by 5% or less of the diseased individuals,” write Paola Nicoletti (Icahn School of Medicine at Mount Sinai, New York) and co-workers in a poster presentation.
“In contrast, ABCB11 accounted for 9% of the AS-DILI risk.”
The team used whole-genome sequencing techniques to look for genetic alterations in men with a phenotype of “bland cholestasis” associated with AS use, characterized by pruritus and elevated bilirubin without an increase in gamma-glutamyl transferase levels.
The study included 93 men who met these criteria, the majority showing jaundice (97.8%), pruritus (80.6%), and nausea (57.0%), while a smaller proportion reported abdominal pain (39.8%), rash (19.4%), and fever (10.8%). Overall, 28.0% of patients were classified as having moderate (icteric) disease, 50.5% as having moderate disease requiring hospitalization, and 21.5% as having severe disease with organ failure.
The men were aged an average of 38.1 years and had an average body weight of 87.9 kg. Although the majority (73.6%) used alcohol, few were positive for hepatitis C (6.5%) or HIV (1.1%), or had an endocrine disorder, such as diabetes (2.0%), or a family history of liver disease (1.1%).
Sixty-one of the participants were non-Hispanic White, 16 were non-Hispanic Black, 16 were Hispanic, and four were Asian, and these were matched by ancestry to a respective 422, 321, 169, and 100 controls from the 1000 Genome Project.
Analysis of 504 genes associated with anabolic steroid metabolism or cholestatic pathways indicated that ABCB11, the gene encoding the bile salt export pump, was significantly enriched for rare damaging variants.
In all, 9% of the men with AS-DILD had alterations in ABCB11 including 7% of non-Hispanic White men, 8% of non-Hispanic Black men, 13% of Hispanic men, and 25% of Asian men. By contrast, just 2% of controls carried alterations to ABCB11, with corresponding rates by ethnicity of 2%, 2%, 1%, and 0%.
Nicoletti et al report that rare damaging variants were detected in two functional domains of ABCB11.
Of note, gene-set analysis looking at the impact of rare damaging variants within the biological pathway that includes ABCB11 indicated that transporters genes associated with bile acid excretion and ABCB11 regulation might also be involved in the genetic susceptibility to AS-DILI cholestasis, the researchers say.
They recognize that the study is “limited by the rare phenotype and lack of AS-exposed controls” but conclude that ABCB11 is a “universally shared risk gene for AS-DILI, as evident by enrichment in damaging coding variants across ancestries.”
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AASLD The Liver Meeting; San Diego, California, USA: 15–19 November 2024